Glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN) are secreted growth factors collectively known as GDNF family ligands (GFLs) (reviewed by Airaksinen and Saarma, 2002). They play a pivotal role in differentiation and maintenance of the nervous system.
The conventional receptor complex for soluble GFLs consists of a ligand-specific glycosylphosphatidylinositol (GPI)-anchored co-receptor GFRα and a signal-transducing module, the receptor tyrosine kinase RET. GDNF activates either RET or NCAM via GFRα1, NRTN activates via GFRα2, ARTN activates via GFRα3 and PSPN uses GFRα4.
Growth factor signaling is modulated by the extracellular matrix (ECM). The activities of many growth factors are affected by interaction with ECM heparan sulfates (HSs) presented by heparan sulfate proteoglycans (HSPGs). Brain development is remarkably dependent on HSPG functioning. The cell surface HSPGs, called syndecans, act as co-receptors for many growth factors and adhesion molecules. Syndecan-3 associates with growing axons and neural processes and is found in most major neuronal migration routes (Kinnunen et al. 1997). Even if GDNF was originally purified by heparin-affinity chromatography (Lin et al., 1993) and shown to interact with HS (Rickard et al., 2003) and to require HS for signaling through the GFRα1-RET complex (Tanaka et al., 2002; Barnett et al., 2002), the molecular identity of HSPGs which bind GDNF and consequently the interaction of NRTN, ARTN and PSPN with heparin or HSPGs has remained obscure. Growth factors have never been demonstrated to signal via HSPG.
Even if GFLs, particularly GDNF, have shown promising results in treatment of Parkinson's disease (Gill et al., 2003) and amyotrophic lateral sclerosis (ALS) (Henderson et al., 1994), other studies have failed to show strong clinical benefits for GDNF (Lang et al., 2006). Also, even if confusion of heparin with GDNF, NRTN or ARTN into rat striatum affected their biodistribution (Hamilton et al., 2001; US 2002/0114780), the mechanism thereof has remained unstudied. Therefore the object of present invention is to found a reason for the above mentioned failure and by unsettling the reason to enable the development of a remedy useful for treating the increasing number of subjects presenting with disorders in the nervous systems.